1. Field of the Invention
The present invention relates to industrially useful 2-aminopyridine derivatives and methods of producing the same.
2. Description of the Prior Art
2-aminopyridine derivatives are useful as starting materials for medicines, agricultural chemicals, and physiologically active materials. In particular, when the nitro group is reduced, 2-amino-3-nitropyridines form 2,3-diaminopyridines which can produce imidazopyridines and pyridotriazols when processed with carboxylic acid and nitrous acid, respectively. These compounds are known to have physiolosical activities.
However, when 2-aminopyridines are nitrated to form 2-amino-3-nitropyridines, the yield of the aimed 3-nitro compounds is low, while a large amount of 5-nitro compounds are formed. Accordingly, it is preferable to use a method comprising the steps of blocking the 5-position of 2-aminopyridines with a halogen atom such as bromine or chlorine, nitrating them to produce 2-amino-3-nitro-5-halogenopyridines (V), and then removing the halogen atom before or after the ring-closure reaction. This method is used in Graboyes et al., J. Am. Chem. Soc., 79, 6421 (1957) and J. B. Ziegler et al., J. Am. Chem. Soc., 71, 1891 (1949).
Nevertheless, even when 2-aminopyridines are halogenated to form 2-amino-5-halogenopyridines (VI), the known methods have many problems.
Namely, B. A. Fox et al (Org. Synth., Col. Vol.5, 346) report the synthesis of 2-amino-5-bromopyridine (VId) by bromination of 2-aminopyridine. However, due to the formation of 2-amino-3,5-dibromopyridine as a by-product, the yield is as low as 62%. Accordingly, such a purifying operation as petroleum ether cleaning is necessary. Also, the above-mentioned Graboyes et al use the method of Case [J. Am. Chem. Soc., 68, 2574 (1946)] and brominate 2-amino-4-methylpyridine in ethanol. Since dibromides are formed in this method, a crude product is washed with ligroin before it is subjected to recrystallization in cyclohexane. This method is industrially unfavorable in that the purificatin process is troublesome. While A. D. Dunn et al [J. Prakt. Chem., 331, 369 (1989)] react 2-amino-4-methylpyridine with hydrogen peroxide in concentrated hydrobromic acid to produce 2-amino-4-methyl-5-bromopyridine (VIa), the yield thereof is as low as 40% while as high as 23% of dibromides are formed as by-products. Also, when 2-amino- 6-methylpyridine is brominated, isomers and dibromides are formed as by-products.
On the other hand, there have been many problems in the conventional methods for chlorinating 2-aminopyridines. For example, in T. Batkowski, Rocz. Chem., 42, 2079 (1968), while 2-aminopyridine is reacted with chlorine in ethanol to form 2-amino-5-chloropyridine, the yield is only 64% and not sufficient. Also, in J. P. English et al., J. Am. Chem. Soc., 68, 453 (1946), while 2-aminopyridine is reacted with chlorine in 20% sulfuric acid, the yield is as low as 54% and the operation is troublesome since by-product, 2-amino-3,5-dichloropyridine, is removed by washing with carbon tetrachloride. Further, in German Patent Publication DE 2,141,634 (1972) to C. Cottel et al, while various 2-aminopicolines are processed with hydrogen peroxide in concentrated hydrochloride so that corresponding 5-chlorinates are synthesized, recrystallization with n-hexane is necessary and the yield is low. In T. J. Kress et al., [J. Org. Chem., 41, 93 (1976) and German Patent Publication DE 2,520,726 (1975)], 2 -aminopicolines are chlorinated in 72% sulfuric acid to form corresponding 5-chlorinates with relatively good yields. However, this method is disadvantageous in that a low reaction temperature (-33.degree. C.) is necessary.
As described in the foregoing, a satisfactory method for producing 2-amino-5-halogenopyridines (VI) has not been known. Also, since their production is difficult, 2-amino-3-nitro-5-halogenopyridines (V), which are their nitro-derivatives, have not easily been produced at a low cost on an industrial scale.